Intermediates in the synthesis of (+) camptothecin and related compounds and synthesis thereof

ABSTRACT

The present method provides a short, convergent total synthesis of novel intermediates in the synthesis of (±)-camptothecin and related compounds. The synthesis scheme includes a novel 4+1 radical annulation followed by another cyclization to simultaneously assemble rings B and C of the Camptothecin compound. In the synthesis, the following novel precursor is reacted with a phenyl isocyanide: ##STR1## The resulting tetracyclic intermediates comprise a quinoline fused to a pyrrolidine ring, with the pyrrolidine ring being fused to an alpha-pyridone ring. The tetracyclic intermediates thus comprise the A, B, C, and D rings characteristic of camptothecin and camptothecin derivatives, and are easily convertible to camptothecin and camptothecin derivatives via hydroxymethylation and oxidation.

This application is a continuation of application Ser. No. 08/085,190,filed on Jun. 30, 1993, abandoned the contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to novel intermediates in the synthesis of(±)-camptothecin and related compounds, and to a synthesis ofcamptothecin and related compounds via a 4+1 radical annulation.

BACKGROUND OF THE INVENTION

As part of an antitumor screening program, Wall and coworkers identifiedthe novel pyrrolo 3,4-b! quinoline alkaloid (S)-camptothecin in 1966.Wall, M. E., et al., J. Am. Chem. Soc., 88, 3888 (1966); Carte, B. K.,et al., Tetrahedron, 46, 2747 (1990). The chemical formula of(S)-camptothecin is provided below. ##STR2## This compound had beenisolated from the extracts of the camptotheca acuminata tree. Inaddition to its novel structure, camptothecin has two other unusualfeatures: its quinoline nitrogen is not very basic, and its α-hydroxylactone is quite reactive. For a few years, camptothecin appeared to bean exciting lead compound for cancer chemotherapy. However, initialmedical excitement waned because of the relative insolubility ofcamptothecin. Moreover, clinical trials of a water-soluble sodium saltderived by opening the lactone of camptothecin were abandoned because ofunpredictable toxicity problems. The sodium salt is considerably lesspotent than camptothecin and its activity is now thought to result fromlactonization to reform camptothecin in vivo.

Camptothecin was synthesized about ten times during the 1970s, althoughsome later syntheses are modifications of earlier ones. Syntheses basedon the Friedlander quinoline synthesis to construct ring B were mostcommon. Ejima, A., et al., J. Chem. Soc., Perkin Trans. 1, 27 (1990);Earl, R. E. and Vollhardt, K. P. C., J. Org. Chem. 1984, 49, 4786;Ihara, M. et al., J. Org. Chem., 48, 3150 (1983); Cai, J. C. andHutchinson, C. R., Chem. Heterocycl. Compd. 25, 753 (1983); Hutchinson,C. R., Tetrahedron 37, 1047 (1981); Cai, J. C. and Hutchinson, C. R.,The Alkaloids: Chemistry and Pharmacology; Brossi, A. Ed.; AcademicPress: New York, Vol. 21, p. 101 (1983); Schultz, A. G., Chem. Rev. 73,385 (1973). Many syntheses are racemic, but resolutions have beenreported. See Wani, M. C., et al. J. Med. Chem., 30, 2317 (1987). Morerecently, a chiral auxiliary approach to asymmetric ethylation wasdescribed. See Ejima, A., et al., Tetrahedron Lett., 30, 2639 (1989).Following the medicinal lead, synthetic interest in camptothecin peakedin the late 70s, and then began to wane.

Oncological and medicinal interest in camptothecin was reborn in the mid80s when details about camptothecin's unique mechanism of action beganto unfold. Camptothecin acts on DNA through the intermediacy of theenzyme topoisomerase I. Hsiang, Y. H., et al., J. Biol. Chem. 260, 14873(1985); Hsiang, Y. H. and Liu, L. F., Cancer Res., 48, 1722 (1988); Liu,L. F., Annu. Rev. Biochem., 58, 351 (1989); "Chemotherapy:Topoisomerases as Targets," Lancet, 335, 82 (1990). The topoisomerasessolve topological problems of DNA. Human topoisomerase I (100 kd)catalyzes the relaxation of supercoiled DNA by cleaving a singlephosphodiester bond to form a temporary phosphoryl tyrosine diester.This intermediate is called the "cleavable complex." The other end ofthe cleaved strand is free, and can "unwind" before the DNA chain isresealed by reverse of the original reaction. Topoisomerase I actswithout cofactors, its reactions are fully reversible, and it is thoughtto be especially important for unwinding DNA (thermodynamicallyfavorable) during replication. In contrast, topoisomerase II acts bycleaving the resealing (after strand passage) both strands of DNA, andits reactions are coupled with ATP hydrolysis.

There is now very strong evidence that camptothecin kills cells bybinding to and stabilizing the covalent DNA-topoisomerase I complex inwhich one strand of DNA is broken (the cleavable complex). Theprogression from the ternary camptothecin/topoisomerase I/DNA complex tocell death is not well understood, and is the subject of intenseinvestigation. Several lines of evidence (including the completereversibility of ternary complex formation) indicate that the ternarycomplex does not simply tie up DNA, but itself actively initiates celldeath. For this reason, camptothecin is often called a "topoisomerasepoison."

Until very recently, camptothecin and its close relatives were the onlyknown topoisomerase I poisons. In contrast, there are now many knownantitumor agents that are topoisomerase II poisons. These include largeclasses of intercalators like the acridines and anthracyclines that wereoriginally thought to interact only with DNA. Such topoisomerase IIpoisons may be inherently less selective than camptothecin because theirinteractions with DNA do not require topoisomerase II. Importantnon-intercalative topoisomerase II poisons include members of thepodophyllotoxin class.

Camptothecin is being touted as an unusually important lead in cancerchemotherapy because of its selectivity. The (potential) selectivetoxicity of camptothecin towards cancer cells emanates from twosources: 1) camptothecin is highly selective for the DNA/topoisomerase Icleavable complex, and 2) replicating cancer cells contain elevatedlevels of topoisomerase I (15-fold increases over normal cells haverecently been measured).

Recent tests in xenografts by Potmesil and coworkers were verypromising. See Giovanella, B. C., et al., Science, 246, 1046 (1989).Racemic 9-aminocamptothecin was found to be very effective in treatingmice carrying colon cancer xenografts. Indeed most of the mice in thestudy were cured by 9-aminocamptothecin at dose levels that were welltolerated. The improved efficacy of 9-aminocamptothecin compared tocurrent drugs used in colon cancer chemotherapy (like 5-fluorouracil)was dramatic. 10,11 -Methylenedioxycamptothecin also showed very goodpromise. Though it is still early, the significance of these results isvery high. Human colon cancer is a major problem in clinical oncology,and one in twenty-five Americans will develop this disease during theirlifetime.

Recent results are even more encouraging. See Giovanella, B. C., et al.,Cancer Res., 51, 3052 (1991). It has been discovered that(S)-camptothecin itself can be formulated in 20% interlipid, and thatthis formulation is active both intramuscularly and orally. Thesetreatments were far superior to the intravenous ones. With thisformulation, non-toxic doses of camptothecin suppressed growth andinduced regression of cancer in thirteen human xenograft lines includingcolon, lung, breast, stomach, ovary, and malignant melanoma.Camptothecin was much less toxic than its sodium salt, and was moreeffective than any other clinical drug tested.

Other close relatives of camptothecin are also emerging as excellentcandidates for chemotherapy against a variety of tumor types. Severalsuch compounds are undergoing clinical trials. Curran, D. P., "TheCamptothecins: A Reborn Family of Antitumor Agents," J. of the ChineseChem. Soc., 40, 1-6 (1993), the disclosure of which is incorporatedherein by reference. See also Sawada, S., Chem. Pharm. Bull., 39, 1446(1991); Giovanella, B. C., et al., Science (Washington, D.C.), 246, 1046(1989); Kingsbury, W. D., et al.; Med. Chem., 34, 98 (1991); Sawada, S.,et al.; Chem. Pharm. Bull., 39, 1446(1991), Nicholas, A. W., et al. J.Med. Chem. 33, 972 (1991).

The excitement about camptothecin recently increased to even greaterlevels upon the discovery that it is a potent antiretroviral agent.Preil and coworkers showed that camptothecin and relatives: 1) inhibitedretroviral topoisomerase I, 2) prevented retroviral infections inhealthy cells, 3) reduced and eliminated retroviral infections andinfected cells, and 4) did not harm cells at useful dose levels. Priel,E., et al., AIDS Res. Hum. Retroviruses 7, 65 (1991). Topoisomerase IIinhibitors were ineffective. These results suggest that camptothecin mayrepresents a new avenue of investigation for the potential treatment ofAIDS.

Given the current interest in camptothecins, new directions in the totalsynthesis of this family of compounds would be welcome.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a short, convergent totalsynthesis of (±)-camptothecin and related compounds using a novel 4+1radical annulation followed by another cyclization to simultaneouslyassemble rings B and C of camptothecin and related compounds.

Generally, the present invention provides a method of synthesizingtetracyclic compounds having the general formula ##STR3## which areintermediates in many syntheses of (±)-camptothecin and relatedcompounds. The conversion of these intermediates to (±)-camptothecin andrelated compounds is accomplished in two steps: hydroxymethylation andoxidation.

The synthesis of the tetracyclic intermediates comprises the step of a4+1 radical annulation wherein the following novel precursor: ##STR4##is reacted with an aryl isocyanide such as phenyl isocyanide. Y ispreferably selected from the group consisting of --N and --CR³. The aryliscyanide may be unsubstituted, monosubstituted, disubstituted ortrisubstituted.

R¹, R², R³ and R⁶ are preferably selected from the following groups:hydrogen, normal and branched alkyl groups, haloalkyl groups,perfluoroalkyl groups, allyl groups, benzyl groups, propargyl groups,alkoxyl groups, halo groups, substituted amino groups, substitutedacylamino groups, cyano groups, acyl groups, substituted hydroxy alkylgroups, substituted amino alkyl groups. R⁴ is preferably selected fromprimary or secondary alkyl, allyl, propargyl and benzyl groups. R⁵ ispreferably selected from linear or branched alkyl groups or benzylgroups. Most preferably, R⁵ is selected from linear or branched alkylgroups in the range of C₁ to C₆.

The present synthetic route is useful for large-scale production ofcamptothecin and the production of new analogs of camptothecin forevaluation of biological activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the reaction scheme for a model 4+1 radicalannulation.

FIG. 2 is an illustration of a synthetic scheme for the synthesis ofcamptothecin via a 4+1 radical annulation.

FIG. 3 is an illustration of the general synthetic scheme of the present4+1 radical annulation.

FIGS. 4a-4g provide illustrations of the chemical structures of severaltetracyclic intermediates.

FIG. 5 is an illustration of a novel camptothecin analogue.

FIG. 6 provides an illustration of a model synthetic scheme for a noveltetracycle.

FIG. 7 provides a synthetic scheme for a novel precursor.

FIG. 8 provides an illustration of the synthetic scheme for a noveltetracycle intermediate.

FIG. 9 provides an illustration of synthetic schemes for preparing arylisocyanides.

DETAILED DESCRIPTION OF THE INVENTION Model Reaction

The viability of the key 4+1 annulation was first demonstrated in themodelreaction shown in FIG. 1.

In the reaction of FIG. 1, readily available bromopyridone 2 wasN-propargylated to give 3. The synthesis of bromopyridone 2 is describedin Newkome, G. R., et al, Synthesis 707 (1974), the disclosure of whichisincorporated herein by reference. In turn, 3 reacted with phenylisocyanideunder conditions similar to those developed for reactions ofsimple pentynyl iodides. These conditions are detailed in Curran, D. P.and Liu, H., J. Am. Chem. Soc. 113, 2127 (1991), the disclosure of whichis incorporated herein by reference.

Generally, an 80° C. benzene solution of 3 (1 equiv), phenyl isocyanide(PhNC) (5 equiv), and hexamethylditin (1.5 equiv) was irradiated with asunlamp for 8 hr. After chromatography, the known tetracycle 4 wasisolated in 40% yield as a white solid.

FIG. 1 also shows a hypothetical mechanism for the conversion of 3 to 4.Addition of pyridone radical 5 to phenyl isocyanide to give 6 isfollowed by two radical cyclizations and an oxidative rearomatization.Curran, D. P. and Liu, H., J. Am. Chem. Soc., 113, 2127 (1991);Leardini, R. et al., J. Org. Chem., 57, 1842 (1992); Bowman, W. R. etal., Tetrahedron, 47, 10119 (1991), the disclosures of which areincorporated herein by reference. See also Stork, G.; Sher, M. M., J.Am. Chem. Soc., 105, 6765 (1983); Barton, D. H. R.; Ozbalik, N.; Vaher,B. Tetrahedron, 44, 3501 (1988).

Synthesis of (±)-Camptothecin

The formal total synthesis of (±)-camptothecin is shown in FIG. 2.Nitrile 8 (dimethyl 3-(cyanomethylidene)pentanedioate) was firstprepared by standard Doebner condensation of dimethylacetonedicarboxylate and cyanoacetic acid (70%). See Simchen, G., Chem.Ber., 103, 389 (1978). A flask equipped with a Dean-Stark waterseparator was charged with benzene (60 mL), dimethylacetone-1,3-dicarboxylate (34.8 g, 0.2 mol), cyanoaceticacid (18.7 g,0.22 mol), acetic acid (5.4 g, 0.09 mol), and ammonium acetate (3.1 g,0.04 mol). The mixture was stirred for 5 minutes and then heated with anoil bath (oil temperature 130°-135° C.) untilno more water wascollected. Heating time was generally 6 hours and the water layercollected was around 6 mL. After the mixture was cooled to roomtemperature, cold water was added. This mixture was then extracted twicewith ether. The combined organic phase was washed with water, saturatedsodium bicarbonate solution, and brine, and dried over sodium sulfate.After removal of solvent, the crude product was purified by vacuumdistillation to give 1.5 g of dimethyl acetone-1,3-dicarboxylate, and27.2 g of nitrile 8 (104°-124° C./0.03 mm) as colorless liquid, yield69-72%. Nitrile 8 was characterized as follows: ¹ H NMR(300 MHz, CDCl₃)δ 5.43 (1H, s), 3.57 (3H, s), 3.55 (3H, s), 3.45 (2H, s), 3.26 (2H, s);¹³ C NMR (75 MHz, CDC13) δ 168.8, 168.5, 151.7, 115.2, 102.6, 52.0 (2C), 40.5, 38.8; IR (neat) 2224, 1738 cm⁻¹.

Standard saponification (KOH/EtOH) gave diacid 9. Conversion of diacid 9tobromopyridone 10 (methyl 2-(6-bromo-2(1H)-pyridon-4-yl) acetate) wasaccomplished by modification of a known method to preparechloropyridones.The diacid was first treated with PCl₅, and then gaseousHBr (10 equiv) was introduced. See Simchen, G., Chem. Ber., 103, 389(1978).

In general, potassium hydroxide (10 g, 180 mmol) was added to a 0° C.solution of nitrile 8 (7.88 g, 40 mmol) in ethanol (160 mL) withstirring. The reaction mixture was stirred at room temperature ("RT")for 2 days. After solvent removal, ice-water (100 mL) was added. Thenthe mixture was immersed in an ice-water bath, and 6N HCl was addedslowly until the pH value reached to 1. This solution was saturated withsodium chloride, and extracted with ethyl acetate (70 mL×4). Thecombined organic phase was dried over sodium sulfate. After solventremoval under reduced pressure (via rotary evaporation and vacuumpumping), 6.87 g of 3-(cyanomethylidene) pentanedioic acid 9 wascollected as yellow or orangesolids.

These solids were crushed to powders and methylene chloride (270 mL) wasadded. The mixture was cooled to 0° C. and charged with phosphoruspentachloride (17.1 g, 82 mmol) under argon. The suspension was stirredatroom temperature until all the white solids dissolved (3-9 h). Theflask was cooled with an acetone-dry-ice bath, evacuated with anaspirator, and sealed.

Gaseous anhydrous hydrogen bromide (about 10 L, 400 mmol) was introducedand absorbed by the solution. The vacuum was then released by fillingthe vessel with argon. The flask was equipped with a drying-tube whichwas connected to a gas trap to absorb excess HBr. The solution wasstirred at -78° C. for 1 h and at room temperature for 8 h. The reactionmixture was cooled to -78° C. again. Anhydrous methanol (15.4 g, 480mmol) was added in one portion. The solution was then slowly warmedtoroom temperature and stirred for 2 more hours. After addition ofice-water (150 mL), two layers were separated. The aqueous layer wasextracted with methylene chloride (100 mL×2). The combined organic phasewas dried over sodium sulfate. After removal of solvent, the residue wasapplied to chromatography (silica gel, CHCl₃ /EtOAC) to give 6.2 g ofbromopyridone 10 as off-white solids, yield 63% (from nitrile 8). Theproduct contained 3-8% of the 6-chloro analogue as detected by GC. ¹ HNMR (300 MHz, CDCl₃) δ 11.82 (1H, Br), 6.81 (1H, d, J=0.8 Hz), 6.60 (1H,d, J=0.8 Hz), 3.73 (3H, s), 3.53 (2H, s); ¹³ C NMR (75MHz, CDCl₃) δ169.7, 165.1, 149.4, 132.0, 117.6, 113.5, 52.6, 40.3; IR (neat) 1728,1647, 1592, 1451 cm⁻¹ ; MS (m/e) 247 (M), 245 (M), 188, 186, 166 (basepeak); HRMS calcd for C₈ H₈ O₃ BrN244.9687, found 244.9661.

N-Propargylation (70%) and C-ethylation (95%) then gave the precursor 11for the 4+1 annulation. For C-ethylation, see Danishefsky, S. andEtheredge, S. J., J. Org. Chem., 39, 3430 (1974), the disclosure ofwhich is incorporated herein by reference.

In general, the solution of bromopyridone 10 (12.3 g, 50 mmol) inanhydrousethylene glycol dimethyl ether (DME, 150 mL) was cooled to 0°C. to -10° C. Sodium hydride (60% suspension in mineral oil, 2.2 g, 55mmol) was added in several portions under argon. The mixture was warmedtoroom temperature and stirred until hydrogen ceased to evolve (about 20min at room temperature). Anhydrous lithium bromide (4.8 g, 55 mmol) wasadded. After 20 minutes, propargyl bromide (80% in toluene, 11.9 g, 100mmol) and DMF (3.7 g, 50 mmol) were added. The mixture was heated at 65°C. for 16 hours. After solvent removal, methylene chloride and waterwere added to the residue. The organic layer was separated. The aqueouslayer was extracted with methylene chloride. The combined organic phasewas washed with water and brine, and dried over sodium sulfate. Aftersolvent removal with a rotary evaporator, a small amount of ether wasadded to the residue, and solids precipitated. The solids were filteredand rinsed with ether to give approximately 9.34 g of methyl2-(6-bromo-N-propargyl-2(1H)-pyridon-4-yl) acetate. The filtrate wasconcentrated and applied to column chromatography (silica gel,hexane/ethyl acetate) to give additional 1.1 g of the product asoff-whitesolids. Total yield was 69-73%. The product contained 3-8% ofthe 6-chloro analogue as detected by GC. ¹ H NMR (300 MHz, CDCl₃) δ 6.50(1 H, d, J=1.6 Hz), 6.43 (1H, d, J=1.6 Hz), 5.02 (2H, d, J=2.4 Hz), 3.72(3H, s), 3.40 (2H, s), 2.29 (1H, t, J=2.4 Hz); ¹³ C NMR (75 MHz,CDCl₃) δ169.6, 161.7, 146.7, 126.3, 118.9, 112.9, 76.9, 72.6, 52.5, 40.1, 38.2;IR (neat) 3287, 1734, 1655, 1597 cm⁻¹ ; MS (m/e) 285 (M), 283 (M, basepeak), 226, 224, 204, 176, 116;HRMS calcd for C₁₁ H₁₀ O₃ BrN 282.9844,found 282.9850.

Under argon, methyl 2-(6-bromo-N-propargyl-2(1H)-pyridon-4-yl) acetate(852mg, 3 mmol) was dissolved in DME (15 mL). The solution was cooled to-60° C., and potassium tert-butoxide (353 mg, 3.15 mmol) was added.After5 min at -60° C., the mixture was warmed to -15° C., then cooled to -60°C. again. Ethyl iodide (1.87 g, 12 mmol) was added. After 5 minutes at-60° C., the reaction mixture was kept inan ice-bath, and stirredovernight (0° C. to room temperature). Solvent was removed with a rotaryevaporator. Methylene chloride (30 mL) and water (30 mL) were added. Theorganic layer was separated. The aqueouslayer was extracted withmethylene chloride. The combined organic phase waswashed with brine, anddried over sodium sulfate. After solvent removal, the residue wasapplied to column chromatography (silica gel, chloroform) to give 890 mgof precursor 11a (methyl 2-(6-bromo-N-propargyl-2(1H)pyridon-4-yl)butyrate) in 95% yield. The product contained 5-10% of the 6-chloroanalogue as detected by GC. ¹H NMR (300 MHz, CDCl₃) δ 6.52 (1H, d, J=1.7Hz), 6.44 (1H, d, J=1.7 Hz), 5.01 (2H, d, J=2.4H),3.69 (3H, s), 3.22(1H, t, J=7.6 Hz), 2.30(1H, t, J=2.4 Hz), 2.00 (1H, m), 1.72 (1H, m),0.90 (3H, t, J=7.4 Hz); ¹³ C NMR (75 MHz, CDCl₃) δ 172.2, 161.7, 151.4,126.3, 117.8, 111.3, 76.8, 72.5, 52.4 (2 C), 38.2, 25.3, 11.9; IR (neat)3264, 1732, 1663, 1509 cm⁻¹ ; MS (m/e) 313 (M, base peak), 311, 284,282, 254, 252, 232, 204, 144;HRMS calcd for C₁₃ H₁₄ O₃ BrN 311.0157,found 311.0139.

Reaction of 11a with phenyl isocyanide as described above gave pure 12ain 45% isolated yield.

Compound 12a was first prepared by Danishefsky, and has been a keyintermediate in many syntheses of camptothecin. See Volkmann, R.Danishefsky, S., Eggler, J. and Soloman, D. M., J. Am. Chem. Soc., 93,5576 (1971); Cai, J. C. and Hutchinson, C. R., Chem. Heterocycl. Compd.,25, 753 (1983); Hutchinson, C. R., Tetrahedron, 37, 1047 (1981); Cai, J.C. and Hutchinson, C. R., The Alkaloids: Chemistry and Pharmacology,Brossi, A. Ed., Academic Press: New York, Vol. 21, p. 101 (1983); andSchultz, A. G., Chem. Rev. 73, 385 (1973), the disclosures of which areincorporated herein by reference. Conversion of 12a to(±)-camptothecinis accomplished in two steps: hydroxymethylation (35%)and oxidation (quantitative). See Cai, J. C. and Hutchinson, C. R.,Chem. Heterocycl. Compd., 25, 753 (1983); Hutchinson, C. R.,Tetrahedron, 37, 1047 (1981); Cai, J. C. and Hutchinson, C. R., TheAlkaloids: Chemistry and Pharmacology, Brossi, A.. Ed., Academic Press:New York, Vol. 21, p. 101 (1983); and Schultz, A. G., Chem. Rev. 73, 385(1973), the disclosures of which are incorporated herein by reference.

This synthesis of the key Danishefsky tetracycle 12a under the presentmethod requires only six steps starting from dimethylacetonedicarboxylate, and the overall yield is currently approximately13%.

A number of analogs of tetracycle 12a can be prepared under the presentsynthesis scheme. The general chemical equation for the 4+1 annulationof the present invention is given in FIG. 3. In FIG. 3, X of precursor11 preferably comprises Cl, Br, or I. Y of precursor 11 may comprise N,or C--R³. Regioisomers are possible when R² of tetracyclic intermediates12 does not comprise hydrogen.

Several examples of preparation of tetracyclic intermediates via thepresent 4+1 annulation involving precursor 11 and an aryl isonitrile areprovided below.

Preparation of Tetracyclic Intermediates Example 1

Under the general procedure, a benzene solution of precursor 11a (methyl2-(6-bromo-N-propargyl-(1H)-pyridon-4-yl)butyrate), phenyl isocyanide(1.5to 5 equiv) and hexamethylditin (0.7 to 1.5 equiv) in a flask (flatflask preferred) was irradiated under argon with a 275 W GE sunlamp or a450 W Ace Hanovia lamp for 4 to 24 hours. Solvent and isocyanide wereremoved under reduced pressure. The residue was applied to columnchromatography (silica gel, dichloromethane/methanol or hexanelacetoneor chloroform/acetone) and/or MPLC (chloroform/ethyl acetate) to givecorresponding tetracyclic intermediate 12a as illustrated in FIG. 4a.

Method A: A solution of precursor 11a (78 mg, 0.25 mmol), phenylisocyanide(129 mg, 1.25 mmol), and hexamethylditin (123 mg, 0.375 mmol)in benzene (25 mL) in a flat flask was irradiated with a 275 W GEsunlamp at 80° C. for 20 hours. Solvent, isocyanide, and other volatilecomponents were removed under reduced pressure. The residue was appliedtoMPLC (EM LiChroprep Si 60, chloroform/ethyl acetate=1.8/1) to give 37mg oftetracycle 12a as illustrated in FIG. 4a. The yield was 45%.

Method B: A solution of precursor 11a (624 mg, 2 mmol), phenylisocyanide (309 mg, 3 mmol), and hexamethylditin (982 mg, 3 mmol) inbenzene (30 mL) in a flat flask was irradiated for 12 hours with a 450 WAce Hanovia lamp.After removal of solvent, isocyanide, and othervolatile components under reduced pressure, the residue was applied tocolumn chromatography (silicagel, hexane/acetone 1.3:1. 1:1) to give 340mg of crude product as brown solids. The crude product was ground withether, filtered, and rinsed withether to give 178 mg of tetracycle 12aas light yellow solids. The filtratewas concentrated and applied to MPLCto give additional 103 mg of tetracycle 12a, in 42% total yield.

Example 2

Following the procedure of Example 1, method A, except paramethoxyphenylisocyanide (166 mg, 1.25 mmol) was substituted for phenyl isocyanide.MPLC(chloroform/ethyl acetate 1:1) afforded 30 mg of tetracycle 12b (asshown in FIG. 4b) as off-white solids in 33% yield. ¹ H NMR (300 MHz,CDCl₃) δ 8.16 (1H, s), 8.03 (1H, d, J=9.3 Hz), 7.40 (1 H, dd, J=9.3, 2.7Hz), 7.21 (1H, d, J=1.0 Hz), 7.09 (1H, d, J=2.7 Hz), 6.58 (1H, d,J=1.0HZ), 5.15 (2H, s), 3.93 (3H, s), 3.69 (3H, s), 3.45 (1 H, t,J=7.6Hz), 2.11 (1H, m), 1.90 (1H, m), 0.93 (3H, t, J=7.3 Hz); ¹³ C NMR(75 MHz, CDCl₃) δ 172.7, 161.3, 158.7, 152.7, 150.4, 146.2, 144.9,130.9, 129.4, 123.4, 129.3, 118.7, 105.4, 100.4, 96.1, 55.6, 53.2, 52.3,49.7, 25.6, 12.0; IR (neat) 1730, 1667, 1601, 1240 cm⁻¹ ; MS (m/e) 364(M, base peak), 336, 305, 278;HRMS calcd for C₁₂ H₂₀ O₄N₂ 364.1423,found 364.1477.

Example 3

Following the procedure of Example 1, method A, except parafluorophenylisocyanide (151 mg, 1.25 mmol) was substituted for phenyl isocyanide.MPLC(chloroform/ethyl acetate 2:1) afforded 29 mg of tetracycle 12c(shown in FIG. 4c) as light yellow solids in 33% yield. ¹ H NMR (300MHz, CDCl₃) δ 8.30 (1H, s), 8.20 (1H, dd J=9.3, 5.4 Hz), 7.55 (2H, m),7.29 (1H, d, J=1.3 Hz), 6.63 (1H, d, J=1.3 Hz), 5.24 (2H, s), 3.71 (3H,s), 3.48 (1H, t, J=7.7 Hz), 2.16 (1H, m), 1.90 (1H, m), 0.95 (3 H,t,J=7.3 Hz); ¹³ C NMR (75 MHz, CDCl₃) δ 172.8, 161.3, 161.2 (J_(CF)=250.8 Hz), 152.7, 152.5, 146.0, 145.7, 132.2 (J_(CF) =8.3 Hz), 130.3,129.7, 128.9 (J_(CF) =10.2 Hz), 120.9 (J_(CF) =26.8 Hz), 119.6, 111.3(J_(CF) =21.9 Hz), 100.9, 53.2, 52.4, 49.7, 25.7, 12.1; IR (neat) 1732,1659, 1599 cm⁻¹ ; MS (m/e) 353 (M+1), 352 (M, base peak), 324, 293,265;HRMS calcd for C₂₀ H₁₇ O₃ FN₂ 352.1224, found 352.1248.

Example 4

Following the procedure of Example 1, method B. A solution of methyl2-(6-bromo-N-(2-pentyn-1 -yl)-2(1H)-pyridon-4-yl)butyrate (510 mg, 1.5mmol) prepared from 10, parafluorophenyl isocyanide (272 mg, 2.25 mmol),and hexamethylditin (737 mg, 2.25 mmol) in benzene (22.5 mL) wasirradiated for 17.5 h. Column chromatography (silica gel, hexanelacetone1.5:1, 1:1) afforded 461 mg of crude product. The product was washedwith ether to give 142 mg of tetracycle 12d (shown in FIG. 4d) as lightyellow solids. The filtrate gave, after concentration and application toMPLC (chloroform/ethyl acetate 1.8:1), 54 mg of tetracycle 12d. Totalyield was33%. ¹ H NMR (300 MHz, CDCl₃) δ 8.18 (1H, dd, J =9.2, 5.6 Hz),7.67 (1H, dd, J=9.9, 2.6 Hz), 7,54 (1H, td, J=9.2, 2.6 Hz), 7.28 (1H,s),6.62 (1H, s), 5.19 (2H, s), 3.70 (3H, s), 3.47 (1H, t, J =7.7 Hz),3.10(2H, q, J=7.6 Hz), 2.14 (1H, m), 1.90 (1H, m), 1.36 (3H, t, J=7.6Hz), 0.94(3H, t, J=7.4 Hz); ¹³ C NMR (75 MHz, CDCl₃) δ 172.7,161.3,161.2 (J_(CF) =250.2 Hz), 152.8, 151.9, 146.4, 146.3, 144.9, 133.0(J_(CF) =9.4 Hz), 127.8 (J_(CF) =12.0 Hz), 127.7, 120.2 (J_(CF) =26.3Hz), 119.3, 107.3 (J_(CF) =23.4 Hz), 100.9, 53.2, 52.3, 49.0, 25.6,23.2, 13.8, 12.0; IR (neat) 1734, 1665, 1601 cm⁻¹ ; MS (m/e) 380 (M,base peak), 352, 321, 294; HRMS calcd for C₂₂ H₂₁ O₃ FN₂ 380.1536, found380.1539.

Examples 5.1-5.3

Further examples of tetracycle analogues obtained by substitution ofvarious aryl isocyanides for phenyl isocyanide and otherwise followingtheprocedure set forth in Example 1, method B, are set forth in FIG.4e-4g. Tetracycle 12e (shown in FIG. 4e) was obtained in 20% yield. Inthe case of the meta-substituted isocyanide reactant shown in FIG. 4f,two isomerictetracycles 12f and 12g were obtained in a 2:1 ratio. Thecombined yield was 22%. Similarly, in the case of the meta-substitutedisocyanide reactant shown in FIG. 4g, two isomeric tetracycles 12h and12i were obtained in a 4:1 ratio. The general formula of FIG. 3illustrates such isomers as 12 and 12'. The combined yield in the caseof tetracycle 12h and 12i was 42%.

Example 5.1

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),para-trifluromethylphenylisocyanide (171 mg, 1 mmol), andhexamethylditin (246 mg, 0.75 mmol) in benzene (10 mL) was irradiatedfor 4 to 12 h. Column chromatography (silica gel, hexane/acetone 2:1,1:1) followed by MPLC (chloroform/ethyl acetate 3.5:1) afforded 41 mg of12e in 20% yield. ¹ H NMR (300 MHz, CDCl₃) δ 8.46 (1H, s), 8.33 (1H, d,J=8.9 Hz), 8.23 (1H, s), 7.97 (1H, dd, J=8.9, 1.6 Hz), 7.37 (1H, d,J=1.0 Hz), 6.68 (1H, d, J=1.0 Hz), 5.29 (2H, s), 3.72 (3H, s), 3.50 (1H,t, J=7.7 Hz), 2.18 (1H, m), 1.91 (1H, m), 0.97 (3H, t, J=7.4 Hz); ¹³ CNMR (125 MHz, CDCl3) δ 172.7, 161.2, 155.1, 152.7, 149.8, 145.3, 131.9,131.0, 131.1, 129.5, (q, J_(CF) =33 Hz), 127.0, 126.2 (2 °C.), 123.8 (q,J_(CF) =271 Hz), 120.4, 101.8, 53.2, 52.5, 49.7, 25.7, 12.1: IR (neat)1732, 1667, 1605, 1171, 1123 cm⁻¹ ; MS (m/e) 403, 402(M, base peak),383, 374, 343, 328, 315.

Example 5.2

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),meta-trifluromethylphenylisocyanide (171 mg, 1 mmol), andhexamethylditin (246 mg, 0.75 mmol) in benzene (10 mL) was irradiatedfor 12 hours. Columnchromatography (silica gel, hexane/acetone 2:1, 1:1)followed by MPLC (chloroform/ethyl acetate 11:1, 2.5:1) afforded 31 mgof 12f and 12g in 22% yield. 12f: ¹ H NMR (300 MHz, CDCl₃) δ 8.67 (1H,s), 8.39 (1H, d, J=8.5 Hz), 8.01 (1H, d, J=7.3 Hz), 7.84 (1H, t, J=7.9Hz), 7.34 (1H, d, J=1.4 Hz), 6.67 (1H, d, J=1.4 Hz), 5.29 (2H, s), 3.72(3H, s), 3.49 (1H, t, J=7.7 Hz), 2.17 (1H, m), 1.91 (1H, m), 0.96 (3H,t, J=7.4Hz); ¹³ C NMR (125 MHz, CDCl₃) δ 172.7, 161.2, 153.6, 152.7,149.0, 145.2, 134.5, 130.3, 128.8, 127.6, 126.7 (q, J_(CF) =31 Hz),126.3, 124.2, 124.0 (q, J_(CF) =272 Hz), 120.2, 101.5, 53.2, 52.4, 50.0,25.7, 12.1; IR (neat) 1736, 1671, 1609, 1306, 1167, 1121 cm⁻¹ ;MS (m/e)403, 402 (M, base peak), 374, 343, 328, 315. 12 g: ¹ H NMR (300 MHz,CDCl₃) δ 8.53 (1H, s), 8.44 (1H, s), 8.06 (1H, d, J=8.6 Hz), 7.82 (1H,dd, J=8.6, 1.4 Hz), 7.35 (1H, d, J=1.4 Hz), 6.69 (1H,d, J=1.4 Hz), 5.30(2H, s), 3.73 (3H, s), 3.50(1H, t, J=7.7 Hz), 2.18 (1H, m), 1.92 (1H,M), 0.97 (3H, t, J=7.4 Hz); ¹³ C NMR (125 MHz, CDCl₃) δ 172.6, 161.2,154.4, 152.8, 147.9, 145.2, 132.2 (q, J_(CF) =33 Hz), 131.0, 130.8,129.4 (2 ° C.), 127.6, 123.8 (q, J_(CF) =271 Hz), 123.4, 120.2, 101.7,53.2, 52.5, 49.8, 25.7, 12.1; IR (neat) 1736, 1665, 1592, 1325, 1188,1165, 1129 cm⁻¹ ; MS (m/e) 403, 402 (M, base peak), 383, 374, 343, 328,315;HRMS calcd for.

Example 5.3

Example 1, method B was followed. A solution of 11a (156 mg, 0.5 mmol),3,4-dimetholxyphenylisocyanide (163 mg, 1 mmol), and hexamethylditin(246 mg, 0.75 mmol) in benzene (10 mL) was irradiated for 12 hours.Column chromatography (silica gel, hexane/acetone/methanol 1:1:0,1:1:0.05) followed by MPLC (chloroform/ethyl acetate/methanol 1:1:0,1:1:0.1) afforded 18 mg of 12i and 66 mg of 12h in 42% total yield. 12i:¹ H NMR (300 MHz, CDCl₃) δ 8.63 (1H, s), 7.98 (1 H, d, J=9.4 Hz), 7.60(1H, d, J=9.4 Hz), 7.26 (1H, d, J=1.5 Hz), 6.62 (1H, d, J=1.5 Hz), 5.24(2H, s), 4.05 (6H, s), 3.71 (3H, s), 3.47 (1H, t, J=7.8 Hz), 2.16 (1H,m), 1.90 (1H, m), 0.95 (3H, t, J=7.3 Hz); ¹³ C NMR (125 MHz, CDCl₃) δ8172.8, 161.4, 152.7, 151.2, 149.4, 146.1, 144.4, 142.1, 128.9, 125.8,125.0, 124.1, 119.2, 118.7, 100.7, 61.5, 56.8, 53.2, 52.4, 50.0, 25.6,12.1, IR (neat) 1732, 1662, 1595, 1267, 1169, 1096 cm⁻¹ ; MS (m/e) 395,394 (M, base peak), 379, 366, 335, 308; 12h: ¹ H NMR (300 MHz, CDCl₃) δ8.19 (1H, s), 7.51 (1H, s), 7.22 (1H, d, J=1.1 Hz), 7.13 (1H, s), 6.60(1H, d, J=1.1 Hz), 5.20 (2H, s), 4.08 (3H, s), 4.06 (3H, s), 3.71 (3H,s), 6.60 (1H, d, J=1.1 Hz), 5.20(2H, s), 4.08 (3H, s), 4.06 (3 H, s),3.71 (3H, s), 3.47 (1H, t, J=7.7 Hz),2.16 (1H, m), 1.90 (1H, m), 0.95(3H, t, J=7.4 Hz); ¹³ C NMR (125 MHz,CDCl₃) δ 172.7, 161.4, 153.3,152.7, 150.9, 150.5, 146.5, 146.1,128.9, 127.6, 124.3, 118.6, 107.9,105.2, 100.1, 56.3, 56.2, 53.2, 52.3, 49.8, 25.5, 12.0; IR (neat) 1736,1667, 1617, 1599, 1503, 1431, 1256, 1225cm⁻¹ ; MS (m/e) 395, 394 (M,base peak), 366, 335, 320, 308.

Example 6.1-6.3

An interesting analogue of camptothecin potentially accessible by thepresent radical 4+1! annulation method is shown in FIG. 5. Thequinoxaline ring system of this analogue would be formed by employing anitrile (rather than an alkyne) as the radical acceptor Y in thepyridone precursor 11 of FIG. 3.

Several examples of synthesis of the requisite pyridinone precursors andthe resulting tetracycle intermediates for the analogue of FIG. 5 andrelated compounds are given below.

Example 6.1

The precursor 11b of FIG. 6 was produced by first cooling a solution of6-bromopyridone (1.0 g, 5.75 mmol) in DME (20 mL) to -60° C.Sodiumhydride (252 mg of a 60% dispersion in oil, washed with hexanesand dried) was then added and the mixture was allowed to warm to roomtemperature. The mixture was stirred for 30 mins., until H₂ evolutionhad ceased. After this time, lithium bromide (550 mg, 6.32 mmol),bromoacetonitrile (1.38 g, 11.5 mmol) and DMF (665 μL) were added. Themixture was then heated at reflux for 16 hours. The indigo-coloredreaction mixture was then concentrated at reduced pressure and theresidue was partitioned between CH₂ Cl₂ (20 mL) and water (20 mL). Theaqueous phase wasfurther extracted with CH₂ Cl₂ (3×20 mL). The combinedorganic extracts were then dried, filtered and concentrated at reducedpressure. Flash chromatography (eluant, 1:1 hexane, ethyl acetate) ofthe crude product and concentration of the fractions containing materialR_(f) =0.1 afforded the product pyridone precursor 11b as a colorlesssolid (730 mg, 64%). This material was recrystallized from CHCl₃ /hexaneto afford colorless needles, mp 100°-101° C. ¹ H NMR (300 MHz, CDCl₃) δ7.23 (dd, J=9.3 and 7.0 Hz, 1H, H4), 6.58 (d, J=9.3 Hz, 1H), 6.56 (d,J=7.0 Hz, 1H), 5.18 (s, 2H). ¹³ C NMR (75 MHz, CDCl₃) δ 161.66, 140.29,125.32, 119.18, 113.80, 111.98, 35.99. IR (KBr) 2999, 2961, 1660, 1583,1512, 800 cm⁻¹. MS m/e 212, 214 (M+), 184, 186 (M--CO), 133 (M--Br).

A solution of pyridone precursor 11b (100 mg, 0.469 mmol) in benzene (10mL) containing hexamethylditin (222 mg, 0.678 mmol) and phenylisocyanide (2.4 mL of a 1.0M solution in benzene) was heated at 80° C.and irradiated with an hanovia UV lamp for 16 hours. After this time themixture was diluted with Et₂ O and shaken with 2M HCl and then filteredthrough a sintered glass funnel. The phases were then separated and theorganic phase was extracted with 2M HCl (6×20 mL). The combined aqueousacidic phases were neutralized with NaOH and extracted with CHCl₃ (4×50mL). The combined organic phases were then dried, filtered andconcentrated at reduced pressure to afford a brown oil(110 mg).Preparative TLC of this material (1:1 acetone, CH₂ Cl₂)and extraction ofthe yellow fluorescent band (R_(f) =0.5) gave the product tetracycle 12jas shown in FIG. 6 as a yellow solid (38 mg, 35%). ¹ H NMR (300MHz,CDCl₃) δ 8.20 (m, 2H), 7.88 (m, 2H), 7.68(dd, J=8.7 and 7.0 Hz, 1H),7.31 (d, J=6.7 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H),5.31 (s, 3H). ¹³ C NMR(125 MHz, CDCl₃) δ 161.20, 152.95, 146.65, 144.22, 142.88, 142.74,140.14, 131.31, 130.69, 129.87, 129.48, 122.25, 102.30, 50.55. IR (KBr)3445, 2363, 2340, 1653 cm⁻¹. MS m/e 235 (M+), 207 (M--CO).

Example 6.2

Precursor 11c of FIG. 7 was produced by first treating a solution ofbromopyridone (1.5 g, 6.10 mmol) in DME (20 mL) at -60° C. with sodiumhydride (267 mg of a 60% dispersion in oil). The mixture was allowed towarm to room temperature, and after evolution of hydrogen had ceasedlithium bromide (585 mg, 6.72 mmol), bromoacetonitrile (1.46 g, 12.18mmol) and DMF (720 μL) were added. The mixture was then heated atrefluxfor 16 hours. After usual workup and chromatographic purification, theproduct was afforded as a colorless solid (0.98 g, 56%, 64% based onrecovered starting material). This material was recrystallized fromCHCl₃ /hexanes to give colorless prisms, mp 107°-109° C. ¹ H NMR (300MHz, CDCl₃) δ 6.57 (s, 1H), 6.47 (s, 1H), 5.15 (s, 2H), 3.74 (s, 3H),3.43 (s, 2H). ¹³ C NMR (75 MHz, CDCl₃) δ 169.17, 161.17, 147.67, 125.05,118.90, 113.71, 113.58, 52.58, 40.14, 35.75. IR (KBr) 3017, 2957, 2361,2342, 1736, 1668, 1593, 1508cm⁻¹. MS m/e 284, 286 (M+), 245, 247 (M--CH₂N), 205 (M--Br, 100).

Example 6.3

A solution of pyridone precursor 11c (533 mg, 1.87 mmol) in DME (8 mL)was cooled to -70° C. KOtBu (0.23 g, 2.05 mmol) was added in oneportion, and the solution immediately turned a bright yellow color.After 5 mins., ethyl iodide (0.62 g, 7.75 mmol) was added and thereaction mixture was stirred for 2 hours at -70° C. and then at roomtemperature for 20 hours. After this time the mixture was poured intowater (20 mL) and extracted with CH₂ Cl₂ (3×20 mL). The combinedextracts were dried, filtered and then concentrated at reduced pressure.The residue obtained was purified by flash chromatography (eluant, 1:1ethyl acetate, CHCl₃) to afford the product 11d of FIG. 8 as a colorlessoil that solidified on standing (400 mg, 65%). This precursor 11d wasrecrystallized from CHCl3/hexanes to afford colorless prisms. ¹ H NMR(300 MHz, CDCl₃) δ 6.55 (s, 1H), 6.42 (s, 1H), 5.12 (s, 2H), 3.66 (s,3H), 3.21 (t, J=7.6 Hz, 1H), 1.97 (m, 1H), 1.68 (m, 1H), 0.87 (t, J=7.3Hz, 3H). ¹³ C NMR (75 MHz, CDCl₃) δ 171.71, 161.11, 152.28, 125.07,117.60, 113.72, 111.84, 52.26, 35.69, 32.52, 25.08, 11.68. IR (NaCl)2967, 2359, 1736, 1671, 1597, 1200, 1169cm⁻¹, MS m/e314, 316 (M+), 233(M--Br, 100).

According to FIG. 8, a solution of the bromopyridinone precursor 11d(120 mg, 0.383 mmol), phenyl isocyanide (2.0 mL of a 1.0M solution inbenzene) and hexamethylditin (180 mg) in benzene (10 mL) was heated at80° C. and irradiated with a Hanovia lamp for 20 hours. The mixture wasthen concentrated and the residue was purified by flash chromatography,(EtOAc/CHCl₃, 1:1). Fractions containing fluorescent material, R_(f)=0.3 were combined and concentrated to afford product tetracycle 12k asa yellow solid (14 mg, 11%). ¹ H NMR (300 MHz, CDCl₃) δ 8.20 (m, 2H),7.88 (m, 2H), 7.35 (s, 1H), 6.71 (s, 1H), 5.28 (s, 2H), 3.73 (s, 3H),3.49 (t, J=7.6 Hz, 1H), 2.16 (m, 1H), 1.90 (m, 1H), 0.97 (t, J=7.3 Hz,3H). ¹³ C NMR (125 MHz, CDCl₃) δ 172.65, 160.95, 153.10, 152.42, 146.51,143.94, 142.84, 142.74, 131.38, 130.95, 129.89, 129.48, 121.05, 102.37,53.19, 52.50, 50.37, 25.64 (one resonance not observed). IR (NaCl) 2973,2386, 1738, 1659, 1651, 1622 cm⁻¹. MS m/e 335 (M+, 100), 307 (M--CO),276 (M--CO₂ Me).

Preparation of Aryl Isocyanides

The aryl isocyanides (e.g., phenyl isocyanide) for reaction withprecursor 11 in the present synthesis are readily available from arylamines by several standard methods as illustrated in FIG. 9. Typically,amines are reacted with base and chloroform (Method A of FIG. 9) or theyare first converted to the respective formamides which are thendehydrated (Method Bof FIG. 9). See Ugi, I., "Isonitrile Chemistry,"Academic Press, NY, 10-17 (1971) and Walborsky, H., Org. Prep. Proced.Int., 11, 293-311 (1979), thedisclosure of which are incorporated hereinby reference.

Reaction of Aryl Isocyanides with Precursor 11

The reaction of precursor 11 with an aryl isocyanide to produce atetracycle intermediate preferably takes place in the presence of acoreactant of the general formula given below:

    R.sub.3 M--MR.sub.3

In the above general formula, M comprises a metal or metalloid.Preferably M comprises Si, Ge or Sn. Most preferably M comprises Sn. Rmay comprise an alkyl or aryl group. Preferably the coreactant compriseshexamethylditin.

Several examples of the reaction of precursor 11a and phenyl isocyanidearegiven in Table 1 for hexabutylditin (Bu₃ Sn)₂, hexamethyldisilane(Me₃Si)₂ and hexamethylditin (Me₃ Sn)₂. The percent yields in Table 1 arefor tetracycle intermediate 12a.

                  TABLE 1                                                         ______________________________________                                        Coreactant                                                                              Phenyl isocyanide                                                                          Temp.   Time    Yield                                  ______________________________________                                         1!                                                                           1.5 eq (Bu.sub.3 Sn).sub.2                                                              5 eq         80° C.                                                                         24 hr.  48%                                    1.5 eq (Bu.sub.3 Sn).sub.2                                                              1.5 eq       RT      24 hr.  35%                                     2!                                                                           1.5 eq (Me.sub.3 Si).sub.2                                                              5 eq         80° C.                                                                         24 hr.  45%                                    1.5 eq (Me.sub.3 Si).sub.2                                                              1.5 eq       RT      24 hr.  28%                                     3!                                                                           1.5 eq (Me.sub.3 Sn).sub.2                                                              5 eq         80° C.                                                                         36 hr.  58%                                    1.5 eq (Me.sub.3 Sn).sub.2                                                              1.5 eq       RT      52 hr.  56%                                    ______________________________________                                    

Metal or metalloid hydrides may also be used as a coreactant.

While presently preferred embodiments of the present invention have beendescribed in detail, the invention may be otherwise embodied within thescope of the appended claims.

What is claimed is:
 1. A method of synthesizing the followingintermediate in the synthesis of camptothecin: ##STR5## comprising thestep of a 4+1 radical anuulation/cyclization wherein the precursor##STR6## is reacted with phenyl isonitrile wherein X is selected fromthe group consisting of Br, Cl and I and wherein R5 is selected from thegroup consisting of an alkyl group and a benzyl group.
 2. The method ofclaim 1 wherein the reaction of the precursor with a phenyl isonitriletakes place in the presence of a coreactant having the formula:

    R.sub.3 M--MR.sub.3

wherein M is selected from the group consisting of Si, Ge and Sn andwherein R is selected from the group consisting of an aryl group and analkyl group.
 3. The method of claim 2 wherein R₃ M--MR₃ ishexamethylditin.
 4. The method of claim 1 wherein X is Br.
 5. The methodof claim 2 wherein R₃ M--MR₃ is hexabutylditin.
 6. The method of claim 2wherein R₃ M--MR₃ is hexabutyldisilane.